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SMP - MIM Part 1 > Lecture 4 - Immunoglobulins > Flashcards

Lecture 4 - Immunoglobulins Flashcards

1
Q

What are the 3 functions of BCRs?

A
  1. Antigen binding
  2. Lectin interactions
  3. Bind to cell surface Fc receptors (important for opsonization) via the portion that activates the complement system
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2
Q

How many types of constant domains do BCRs have? List them. What do we call these?

A
  1. IgM
  2. IgD
  3. IgG
  4. IgE
  5. IgA

= isotypes

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3
Q

Other name for antibody?

A

Immunoglobulin

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4
Q

What cells secrete BCRs?

A

Plasma cell = terminally-differentiated B cell

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5
Q

What kind of molecules are antibodies?

A

Glycoproteins

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6
Q

How many AAs in one antibody domain?

A

110 AAs

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7
Q

What are lectins?

A

Proteins that bind carbohydrates

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8
Q

What is the difference between a BCR and an antibody?

A

BCR is membrane bound

Antibody is secreted

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9
Q

Describe the structure of antibodies.

A

Divided into sections:

  1. Variable regions: bind antigen and are at the N-terminal of the light and heavy polypeptide chains => 110 AA long and vary extensively in amino acid sequence among antibodies with different antigen-binding specificities
  2. Constant regions: bind complement and Fc receptors, carboxy-terminal portion, are shared by many antibodies, and are divided into segments (each 110 AAs):
    - CH1 domain = the first amino-terminal region in the HC constant region
    - CH2 = the second amino-terminal region in the HC constant region
    - ETC.
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10
Q

What are antibody light chains made of?

A

One variable domain (VL) + one constant domain (CL)

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11
Q

2 types of light chains on antibodies? What to note? Which one is more common in humans?

A
  1. Kappa (twice as more)
  2. Lambda

Different because can recognize different epitopes

Note: they are functionally identical

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12
Q

How many constant domains do antibodies have?

A

1-4

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13
Q

What is the hinge region? Purpose? What to note?

A

Area between CH1 and CH2 that is highly flexible as it contains many proline AAs enabling the arms of the antibody to move in space AND makes the monomer particularly susceptible to proteolytic cleavage (papain and pepsin cleave in this region)

Note: region varies in length in different HC

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14
Q

How are the heavy chains of antibodies held together?

A

Disulfide bonds between cysteine residues in the hinge region

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15
Q

How are the heavy chain and light chain of antibodies held together?

A

One disulfide bond between cysteine residues

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16
Q

Length and weight of antibody heavy chains?

A
  1. MW = 50,000-70,000 daltons

2. ~440 or 550 amino acids long

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17
Q

Length and weight of antibody light chains?

A
  1. MW = 25,000 daltons

2. ~220 amino acids long

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18
Q

Can antibody monomers be linked together?

A

Sometimes

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19
Q

What is the Fab domain of an antibody? What does it stand for?

A

Variable domain + CH1/CL

= fragment with antigen-binding ability

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20
Q

What is the Fc domain of an antibody? What does it stand for?

A

Constant region of the antibody starting at the hinge region

= fragment crystallizable

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21
Q

How many Fab domains on one antibody?

A

TWO

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22
Q

What is the Fab’ 2 domain of an antibody?

A

Bivalent fragment obtained by cutting the 2 Fab domains below the hinge region

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23
Q

Which 2 antibody isotypes have 4 constant domains?

A
  1. IgM

2. IgE

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24
Q

Which 2 antibody isotypes lack a hinge region?

A
  1. IgM

2. IgE

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25
Q

Which 3 antibody isotypes have 3 constant domains?

A
  1. IgD
  2. IgG
  3. IgA
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26
Q

How many IgG subclasses?

A

4

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27
Q

How many IgA subclasses? Describe where they are found.

A
  1. IgA1
  2. IgA2

Blood: IgA1
Secretions: slight bias toward IgA1 in IgA1:IgA2 ratio

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28
Q

What form is IgM secreted as? Role?

A

Pentamer with identical antigen binding sites => 5 monomers are linked together by interchain S-S and a polypeptide called the J or joining chain

Role: because the pentamer has 10 antigen combining sites, 2 per monomer, it is very good at binding antigens with repeating subunits and causing agglutination (clumping) + activates complement system

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29
Q

What form is IgA secreted as?

A
  1. Blood: monomer
  2. External secretions (tears, milk, saliva, mucus): dimer or higher order polymer => monomers are linked together by interchain S-S and a polypeptide called the J or joining chain + part of the polyIg receptor remains attached to IgA as a secretory piece/component (a glycoprotein)
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30
Q

What gene segments does the variable domain of a light chain consist of?

A

Consists of a V (variable) and a J (joining) gene segment

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31
Q

What gene segments does the variable domain of a heavy chain consist of?

A

Consists of a V (variable), D (diversity) and J (joining) gene segment

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32
Q

AA length of one variable domain (light or heavy) of an antibody?

A

~113 AAs

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33
Q

How many AAs does the V gene segment of an antibody variable domain code for?

A

~100 AAs

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34
Q

How many AAs do the J and D gene segments of an antibody variable domain code for?

A

Each ~13 AAs

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35
Q

How are different V, J, and D gene segments arranged together in variable domains of antibodies? What does this allow?

A

At random

This allows the immune system make antibodies with endless different specificities

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36
Q

On what 3 chromosomes are the Ig heavy and light chain loci found?

A

Chromosomes 22, 2, and 14

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37
Q

What Ig loci are found on chromosome 22? Describe their organization.

A

Lambda light-chain loci:

  1. 29-33 V gene segments
  2. Series of alternating J gene segments and constant domains (4-5 of each)
38
Q

What Ig loci are found on chromosome 2? Describe their organization.

A

Kappa light-chain loci:

  1. 34-38 V gene segments
  2. 5 J gene segments
  3. 1 constant domain

Each type of gene segment grouped together in sequence

39
Q

What Ig loci are found on chromosome 14? Describe their organization.

A

Heavy-chain loci:

  1. 38-46 V gene segments
  2. 23 D gene segments
  3. 6 J gene segments
  4. 9 constant domains

Each type of gene segment grouped together in sequence

40
Q

What happens to the intervening DNA in between the gene segments selected for a particular variable region of an Ig?

A

Spliced out

41
Q

What are regions of hypervariability in variable domains of antibodies? What encodes each? Are these on both light and heavy chains?

A
  1. HV1 ~30-40th residue encoded for by V gene segment
  2. HV2 ~50-60th residue encoded for by V gene segment
  3. HV3 ~90-100th residue encoded for by both the V and J gene segments (where they meet)

YUP

42
Q

In how many areas in variable domains of antibodies is variability low? What are these called?

A

Framework regions:

  1. FR1
  2. FR2
  3. FR3
  4. FR4
43
Q

Other name for hypervariable domains of variable domains of Igs?

A

Complimentarity-determining regions (CDR)

44
Q

Which hypervariable domain is the most variable? Why?

A

HV3 because there is addition and subtraction of nucleotides to join the V and J gene segments, which increases the AA diversity in this region

45
Q

Where are hypervariable regions located?

A

In discrete loops of the folded structure of the variable domain of the antibody joining anti-parallel beta-pleated sheets

46
Q

What portions of the antibody are in contact with the epitope?

A

Hypervariable regions of the variable domain of the antibody: HV1, 2, and 3 on both the light and heavy chain

47
Q

What defines the specificity of an antibody?

A

Hypervariable regions of the variable domain of the antibody

48
Q

4 mechanisms by which antibody diversity is generated? Describe each. Do these apply to TCRs?

A
  1. Combinatorial 1: joining of different V (D) and J segments to form functional H and L variable domains
  2. Combinatorial 2: joining different heavy and light chains together
  3. Junctional: addition/subtraction of nucleotides at V-J joint of L chain and V-D-J joints of H chain
  4. Somatic hypermutation: cytokines from FH T cells in germinal centers drive point mutations in the variable domain of H and L chains => B cells with mutations that result in increased specificity are selected to proliferate

1-3 YES, but NOT 4

49
Q

What is class or isotype switch and how does it occur? Example?

A

There are specific sequences called switch sequences in the DNA preceding the constant region exons of each class of heavy chain (except delta) and activation of the B cell can stimulate a recombination event that alters the class of constant region expressed (moving a constant domain to the most 5’ region), which changes the class of the antibody expressed from IgM to either IgG, IgA or IgE

The rearranged VDJ segment is spliced next to one of the other C regions downstream of delta depending on specific cytokines produced by FH T cells in germinal centers acting on the B cell

For example: IL-4 promotes the switch to either IgG1 or IgE while IL5 promotes the switch to IgA

50
Q

What diseases are associated with defects in isotype switch?

A

Immunodeficiencies

51
Q

What determines what kind of cytokines a FH T cell secretes in secondary lymphoid tissues?

A

Depending on the antigen presented by dendritic cells

52
Q

Does isotype switching change the specificity of the antibody?

A

NOPE

53
Q

Which antibody isotype is the first one produced in an immune response? Why?

A

IgM and IgD (depending on splicing)

Because their production does not require isotype swtiching

54
Q

What 2 receptors are expressed on the surface of B cells during development?

A
  1. Monomeric IgM

2. Monomeric IgD

55
Q

What antibodies predominantly mount the primary immune response?

A

IgMs

56
Q

3 functions of IgM? Overall?

A
  1. Neutralization +
  2. Opsonization +
  3. Activates complement system +++

OVERALL: rapid control of a bloodstream infection

57
Q

Functions of IgD?

A

None other than expressed on the surface of B cells during development

58
Q

5 functions of IgG1?

A
  1. Neutralization ++
  2. Opsonization ++
  3. Sensitization for killing by NK cells ++
  4. Sensitization of mast cells +
  5. Activates complement system ++
59
Q

3 functions of IgG2?

A
  1. Neutralization ++
  2. Opsonization *?????
  3. Activates complement system ++
60
Q

5 functions of IgG3?

A

Same as IgG1, except twice as good at activating the complement system

61
Q

2 functions of IgG4?

A
  1. Neutralization ++

2. Opsonization +

62
Q

3 functions of IgA? Overall?

A
  1. Neutralization ++
  2. Opsonization +
  3. Activates complement system +

OVERALL: protection of mucosal surfaces by neutralizing

63
Q

Function of IgE? Overall?

A

Sensitization of mast cells +++

OVERALL: found on mast cells to protect against parasites beneath epithelial surfaces (respiratory, GI, skin) and for allergen removal

64
Q

What antibodies predominantly mount the adaptive immune response?

A

IgGs

65
Q

What 3 antibody isotypes have the highest mean serum levels?

A
  1. IgGs (IgG1 the most)
  2. IgA
  3. IgMs
66
Q

Which 2 antibody isotypes can transport across an epithelium?

A
  1. IgM +

2. IgA +++

67
Q

In what form does IgA transports across an epithelium?

A

Dimer

68
Q

Which 4 antibody isotypes can transport across the placenta?

A
  1. IgG1 +++
  2. IgG2 +
  3. IgG3 ++
  4. IgG4 (some)
69
Q

Which 7 antibody isotypes can diffuse into extravascular sites?

A
  1. IgM (some)
  2. All 4 IgGs +++
  3. IgA ++
  4. IgE +
70
Q

In what form does IgA diffuse into extravascular sites?

A

Monomer

71
Q

What does opsonization mean?

A

Help phagocytes pick up particles

72
Q

Where are IgEs and IgAs found?

A

Barrier epithelia

73
Q

Where are IgGs found?

A

Everywhere

74
Q

Name of IgM heavy chain?

A

Mu heavy chain

75
Q

Name of IgG heavy chain?

A

Gamma heavy chain

76
Q

What % of serum Igs are IgGs?

A

75%

77
Q

Which Igs have the longest plasma half life?

A

IgGs

78
Q

Which antibody isotype is the prototype of an antibody monomer?

A

IgGs

79
Q

How do IgG subclasses differ? Example?

A

The majority of the differences between the subclasses are found in their hinge region in which they differ in size, sequence, position, and number of S-S bonds

Example: IgG3 has a very long hinge region with 11 S-S bonds, while IgG1 has a much shorter hinge region with only 2 S-S bonds => this is why IgG3 is more susceptible to proteolytic cleavage and has a shorter half life

80
Q

Purpose of IgGs binding to Fc receptors?

A
  1. Antigen bound by IgGs binds to Fc receptors on macrophages and other phagocytes => opsonization
  2. Complement activation
81
Q

4 steps of opsonization?

A
  1. Antibody-coated antigen binds to Fc receptors on macrophages and other phagocytes
  2. Macrophage membrane surrounds antigen
  3. Macrophage membranes fuse, creating a membrane-bounded vesicle = the phagosome
  4. Lysosomes fuse with the phagosome creating a new vesicle = the phagolysosome
82
Q

What holds the IgA dimer at the mucosal surface?

A

The carbohydrates of the secretory piece by binding to mucins in mucus

83
Q

Which 2 antibody isotypes have the J chain?

A
  1. IgM
  2. IgA

= polymeric Igs

84
Q

Name of IgA heavy chain?

A

Alpha heavy chain

85
Q

Name of IgE heavy chain?

A

Epsilon heavy chain

86
Q

Principal phagocytes in destruction of bacteria?

A

Macrophages and neutrophils

87
Q

Principal immune cells in destruction of parasites? How are they activated?

A

Eosinophils, mast cells and basophils

IgE bound parasite is detected by eosinophils bearing Fc receptors for IgE => eosinophils release toxic substances that damage the parasite => degranulation causes vasodilation, smooth muscle contraction, release of mediators and influx of inflammatory cells to attack the parasite

88
Q

Can parasites be phagocytosed?

A

Often too large

89
Q

Which 3 immune cells have high affinity Fc receptors?

A
  1. Mast cells
  2. Basophils
  3. Eosinophils
90
Q

Describe IgEs’ role in allergic response? What is this called?

A

When exposed to antigen/allergen and cross-linked, the IgE linked to FcRs sends activation signals => mast cells and basophils degranulate => release of histamine => immediate hypersensitivity reactions (responsible for symptoms of hay fever, hives, anaphylactic shock)

91
Q

What determines which AB isotype it is?

A

Dominant chain on heavy chain

SMP - MIM Part 1 (14 decks)

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